Targeting selenoprotein dependency of AML

 Selenium is an essential trace element incorporated into organisms in the form of selenocysteine (Sec), known as the 21st amino acid, to produce selenoproteins. Sec is encoded by the UGA codon, employing a dedicated Sec biosynthesis pathway to insert Sec into nascent polypeptides instead of terminating translation. Humans have 25 selenoproteins, many of which are involved in redox metabolism such as glutathione peroxidases (GPX) and thioredoxin reductases. We recently showed that the selenoprotein biosynthesis pathway governed by SEPHS2 is critical for acute myeloid leukemia (AML) progression and the maintenance of AML-initiating cells. SEPHS2 itself is a selenoprotein and is regulated by an AML-specific enhancer bound by AML transcription factors such as MYB. Transplantation of murine and human AML cells after deleting SEPHS2 with CRISPR revealed that SEPHS2 is required for leukemogenesis in vivo. Manipulating dietary selenium availability by feeding AML recipient mice with selenium-deficient diet also suppressed leukemogenesis without affecting hematopoiesis, suggesting that selenium restriction may offer a therapeutic window for AML. Mechanistically, we found that SEPHS2 deletion or selenium restriction reduced the expression of GPX4 and increased oxidative stress in AML. I will discuss our recent findings on the selenoprotein biosynthesis pathway and ferroptosis, a newly discovered cell death mechanisms induced by lipid peroxidation, as novel AML vulnerabilities.